Introduction of medical devices implanted into the body can lead to serious nosocomial infections. Implanted medical devices (e.g., venous and arterial catheters, neurological prostheses, shunts and stents, joint implant prostheses, urinary “Foley” catheters, peritoneal catheters, lead wires to pacemakers, etc.), while sterilized and carefully packaged to guard against introduction of pathogens during implantation, pose a risk during insertion, and subsequently. During insertion bacteria can be picked up from the skin and carried into the insertion site where colonization ensues. In the case of urinary catheters, especially those used long term, there is a significant threat of microbial growth along the exterior surface of the catheter. This can lead to chronic urinary tract infections (CUTI), especially among the elderly. Methods aimed at circumventing this problem have included, for example, the coating of implant devices with antibiotics before insertion, irrigating the implant site with antibiotic, applying various antibiotic ointments or antibiotic impregnated sponges near the exterior opening by which infection most likely occurs, impregnating the polymer base coating the implant device with antibiotics, or treatment of patients systemically with antibiotics. However, despite the foregoing attempts and the overuses of antibiotics involved (with the attendant risks of developing resistant strains of bacteria), there remains a need in the art to mitigate the risk of infection from such devices that are implanted and have external environment exposure.
Long term use or misuse of antibiotics often results in the selection of antibiotic resistant strains. Hence, in general, systemic antibiotic therapy is ill advised and ineffective in warding off CUTI. The secondary side effects of systemic antibiotic treatments can also pose a serious risk to many patients. Furthermore, in many implant sites, the formation of fibrous tissue around the implant site reduces the supply of blood to the implant cavity thereby precluding systemic antibiotic treatment of the critical space between the implant and capsular endothelial wall. In the case of a urinary catheter (e.g., Foley catheter), antibiotics injected as a coating in the urinary canal may be washed out during drainage through leakage of some urine along the urinary tract outside the catheter, or resorbed before they can achieve sufficient levels to effectively kill bacteria growing within localized regions of the urinary tract.
Aside from implants, there are other commonly acquired infections that cause significant suffering and health complications in the general population. Vaginal infections, for example, are a frequent cause of health problems in women. They are a source of distress and discomfort, and can lead, in some instances, to sterility, to tubal ectopic pregnancy, and increased incidences in the transmission of human immunodeficiency virus (HIV). Chlamydia trachomatis, a sexually transmitted bacterium, is a serious problem in that it can infect young women of child-bearing age without producing any initial overt symptoms, but causing extensive scaring of the cervix and permanent loss of fertility. Other serious infections acquired during, or prior to pregnancy, but undetected, can result in a multitude of complications to the unborn fetus, or lead to pPROM (preterm premature rupture of membranes before the onset of labor), a major factor contributing to preterm births.
The most common vaginal infections among women are bacterial vaginosis (BV) (sometimes referred to as nonspecific vaginitis or Gardnerella-associated vaginitis), trichomoniasis (sometimes referred to as “trich”), and vulvovaginal candidiasis (VVC) (sometimes referred to as candidal vaginitis, monilial infection, or vaginal yeast infection). In infections associated with pPROM, certain women are prone to colonization by group B Streptococcal strains that pose a particularly serious threat in terms of premature delivery and life-threatening complications to the fetus.
Microbicidal treatments for vaginal infections include oral prescription medications and over the counter (OTC) topical applications, suppositories and douches. Topical medications are messy to apply, and require daily applications over a period of up to a full week. A difficult problem in the use of OTC medications is that the infection may be misdiagnosed and treated inappropriately, resulting in more complicated problems for the user. Some women, for example, inadvertently treat for yeast infections with OTC medications, applying antifungal agents to bacterial infections (including STDs) which are not responsive to this mode of treatment, and thus fail to obtain timely medical treatment.
These problems underscore the need for better treatment devices and for devices designed for prevention of chronic acquired infections associated with implant insertion into body cavities, and, for example, the treatment of BV and pPROM.
Additionally, there is a need for female-controlled contraceptive methods that are effective against pregnancy and infection. There is widespread recognition of the burden of unplanned pregnancies, and the spread of (sexually transmitted diseases) STDs (including AIDS) in contributing to human suffering worldwide. Although tubal ligations and vasectomies provide effective treatments in eliminating unplanned pregnancies, neither provides adequate protection against the spread of STDs (Armstrong, Morbidity Mortality Weekly Report 41:149, 1992). Also, these methods are generally irreversible, rendering them unacceptable to many couples who intend, in the future, to have children. Hormonal methods of birth control (e.g., Norplant®, oral contraceptives, DMPA, vaginal ring), while efficacious in reversibly blocking unwanted pregnancies, offer limited protection against STDs (Cates and Stone, Family Planning Perspectives 24:75–84, 1992). Spermicidal agents, chiefly nonoxynol-9 and varying analogues of this detergent, have a number of drawbacks including irritation of the vaginal mucosal tissues, rapid adsorption across mucosal tissues, and nonspecificity in disrupting indiscriminately the lipid bilayers of cells. There is also some evidence that mucosal lesions of the vagina and cervix, induced by frequent use of nonoxynol-9, facilitate the transmission and spread of the HIV virus. In addition, the use of detergents, such as nonoxynol-9, in combination with diaphragms, cervical caps and condoms is problematic in that they can weaken and degrade the polymers used in the fabrication of these barrier devices. Moreover, diaphragms and cervical caps offer only limited protection against STDs, and have failure rates in terms of unplanned pregnancies in the range of 12 to 24% (Speroff and Darney eds. A Clinical Guide for Contraception, 2nd edition. Williams & Wilkins, Baltimore, Md. pp. 229–262, 1996; and Mauk et al. Contraception 53:329–335, 1996).
Of all the current birth control methods available, the male condom is the only device that has FDA labeling indicating it is effective in reducing the transmission of STDs. However, the male condom fails to address the need for a female-controlled birth control method that further limits exposure to both STDs and unplanned pregnancies.
An important aspect of an effective contraceptive is that it does not require frequent attention, or particular skills in its proper use. Indeed, methods requiring daily attention prior to intercourse have practical failure rates two-fold higher (or higher in some instances) than predicted under ideal use. As an example, the male condom has an expected failure rate, in terms of unplanned pregnancies per year, in the range of 3%, but a practical failure rate in the range of 14%. This failure rate compares with the “natural” withdrawal rate that is in the range of 19%. Of those methods requiring the least attention (e.g., sterilization, hormonal methods, and IUD), while effective, they are inadequate in providing full protection against the spread of STDs. Further, many women dislike long term use of hormonal methods of birth, and they have an aversion to the use of IUD's, in part, because of evidence that IUD's can cause pelvic inflammatory disease and ectopic pregnancies (e.g., the “Dalkon Shield” experience). Thus, there is a need in the art for improved birth control methods that are more effective and convenient to use, which are also safe, and which block the transmission of infectious diseases.
Iodine as an Anti-Infective Agent
In the treatment of infections, elemental iodine is of significance as a prospective anti-infective agent. Iodine has intrinsic chemical properties which could be exploited in conferring to implant devices novel and efficacious anti-infective activities in the treatment, and prevention, of opportunistic infections. Iodine has been used for over 150 years in various formulations as a sterilizing agent.
Iodine exists in several oxidation states including its fully reduced iodide (I−) state, its diatomic elemental state (I2) (hereafter “elemental iodine”), and in several higher oxidation states in combination with oxygen (e.g., hypoiodate (IO−), iodate (IO3−) and periodate (IO4−)). In aqueous solutions iodide forms an equilibrium complex with elemental iodine, yielding soluble tri-iodide (I3−) which exhibits neither significant microbicidal nor virucidal activity. On the other hand, trace quantities (e.g., a few ppm) of elemental iodine are sufficient to cross the lipid bilayer of cells, and sufficient to kill micro-organisms through oxidative reactions within their lipid bilayer. Extensive studies have also shown that microorganisms are incapable of developing resistance against elemental iodine because of its ability to oxidize and intercalate into multiple sites within microbes.
Problems in the Delivery and Formulation of Iodine as an Anti-Infective Agent
Early attempts at improving formulations in extending the shelf life of iodine solutions designed for anti-infective treatments used alcohol as a carrier in trapping iodine in solution. The formulations, referred to as tincture of iodine, proved unsatisfactory because the high alcohol content required to retain elemental iodine in solution proved, itself, inflammatory. A more satisfactory method of trapping elemental iodine in solution evolved with the development of iodophors of iodine (e.g. complexed forms of elemental iodine in solution using specific organic binding agents). Among the better known iodophors formulated to create a potent anti-infective iodine solution was povidone-iodine, also known as Betadine®, a water soluble polyvinylpyrrolidone organic polymer mixed with iodide and elemental iodine. In this formulation elemental iodine binds to the hydrophobic polyvinylpyrrolidone backbone as well as to the cationic pyrrole nitrogen in the form of a tri-iodide complex. The rationale to this formulation was that elemental iodine would be available through equilibrium with loosely bound (e.g., “available”) iodine complexed to polyvinylpyrrolidone.
Elemental iodine (i.e., free I2) is actually only a very small fraction of the total iodine in commercial anti-infective formulations, such as povidone-iodine. 10% povidone-iodine, for example, is formulated at ˜1% total “available” iodine (e.g., 10,000 ppm), whereas its elemental iodine concentration varies from ˜0.8 to 1.2 ppm (Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning, 2nd edition). While this level of elemental iodine is marginally effective as a microbicide, it comes at a cost. LeVeen et al. (Surgery, Gynecology & Obstetrics 176:183–190, 1993) have pointed out several deficiencies in povidone-iodine formulations including the tradeoff of a very low elemental iodine level (e.g., approx. 1 ppm). Low elemental iodine makes povidone-iodine relatively ineffective as an anti-infective agent except against extremely sensitive bacteria. Povidone-iodine solutions also fail to treat severe vaginitis, and cause complications associated with formation of granulomas in wounds, as a result of residual polyvinylpyrrolidone in formulations applied to the wound site.
Additionally, elemental iodine is not available in sufficient concentrations in commercial formulations to use as a spermicidal agent. WHO (the World Health Organization) defines standards for spermicide testing and requires that a spermicide completely immobilize all sperm with which it comes into contact within 20 seconds. These standards reflect the fact that sperm spend a very short time (seconds) within the vaginal vault following ejaculation into the vagina before passing through the cervical os. Thus, an effective spermicide must be capable of rapidly immobilizing sperm before they can pass through the cervical os and into the uterus. These WHO criteria are an important standard for testing contraceptive devices. Others have sought to use iodine formulations in birth control applications either in the form of povidone-iodine, in complexes with polyurethane, or in combination with nonoxynol-9, but have failed to demonstrate adequate spermicidal activity in accordance with the standards defined by WHO. For example, povidone-iodine in the range of 1% and higher total iodine was found to require upwards of 10 minutes exposure to semen samples before the sperm lost motility, whereas 0.1% and lower concentrations of povidone-iodine failed, or even stimulated, sperm motility (Pfannschmidt et al. U.S. Pat. No. 5,545,401). Several patents have disclosed the use of povidone-iodine (or iodine complexed with polyurethane) as a spermicide or in combination with ionic or nonionic detergents (see, for example, U.S. Pat. Nos. 5,545,401; 5,577,514; 4,922,928; 5,156,164; and 5,466,463). However, there is no evidence that iodine formulations of the type disclosed, in any fashion, confer enough spermicidal activity sufficient to put these formulations into practice according to WHO criteria.
Other characteristics of povidone-iodine also make it impractical to use as an intravaginal anti-infective agent, even in combination with other spermicidal agents. For example, the intense brownish-red coloration of this solution makes it unattractive esthetically and unacceptable to users. In addition, the use of povidone-iodine formulations, in combination with such spermicidal detergents as nonoxynol-9, is problematic in that iodine causes the detergent moiety to precipitate out of solution. In the presence of quaternary ammonium detergents, both iodine and triiodide form insoluble complexes in binding to the quaternary ammonium moiety that causes the detergent to precipitate out of solution. Hence, combining iodine with the common spermicidal detergent, nonoxynol-9, related polyunsaturated detergent polymers, or cationic quaternary ammonium detergents produces products that lose their spermicidal properties through chemical modification and precipitation from solution.
An attempt to circumvent problems associated with formulations containing povidone-iodine in recognition of the fact that elemental iodine is the active agent conferring anti-infective activity was made by Shikani and Domb (J. Amer. College of Surgeons 183:195–200, 1996; U.S. Pat. No. 5,762,638). The authors coated plastic implant devices with layers of elemental iodine dissolved in a polymer base in such a manner so as to cause adherence of the iodine-polymer on the surface of the implant device. This approach has several limitations. It is costly and, as pointed out by Shikani and Domb, it is limited to polymeric implant devices which can tolerate solvents used in dissolving the iodine-loaded polymer coating, and which are chemically compatible in forming a strong and intact bond between the iodine impregnated polymer coating and implant polymer substratum. Polymers which swell in biological fluids (a common phenomenon) also cannot be used in this technology because swelling leads to a rupture of the coated outer layer, and thereafter a failure of the controlled release rates of the impregnated iodine to the surrounding sites requiring anti-infective treatment.
Within the body, a variety of naturally occurring oxidants are produced which function as anti-infective agents. The major source of oxidizing activity accounting for development of anti-infective activities in the body can be traced to the initial formation of superoxide and hydrogen peroxide through a variety of oxidizing pathways. These initial oxidants are known to catalyze in the presence of halides, trace metals, thiocyanate (a natural constituent of particular abundance in saliva believed to confer to the mouth certain unique antimicrobial properties when converted to hypothiocyanite), and amines, a cascading armada of anti-infective products including (in addition to superoxide and hydrogen peroxide) hydroxyl radicals, hypohalites (e.g., hypochlorite, hypobromite), haloamines (e.g., chloramine), hypothiocyanite, and nitric oxide, all of which have been shown to exhibit varying degrees of antimicrobial activity (Klebanoff, S. J. and Clark, R. A. (1978) in The Neutrophil: Function and Clinical Disorders, North-Holland Publishing Company, Amsterdam; Halliwell, B. and Gutteridge, J. M. (1990) Role of Free Radicals and Catalytic Metal Ions in Human Disease: An Overview. Meth. Enzymol. 186, 1–85; Southorn, P. A. and Powis, G. (1988) Free Radicals in Medicine. I. Chemical Nature of Biological Reactions. May Clinic Proc. 63, 390–498; Pryor, W. A., ed., in Free Radicals in Biology, Academic Press, New York, 1976–1984), Vol. 1–6; Klebanoff, S. J. (1991) in Peroxidases in Chemistry and Biology (Everse, J., Everse, K. E. and Grisham, M. B., eds.), pp. 1–35, CRC Press, Boca Raton; Tenovuo, J. (1997) Salivary Parameters of Relevance for Assessing Caries Activity in Individuals and Populations. Community Dent. Oral Epidemiol. 25: 82–6; Carlsson, J., Edlund, M. B. and Hanstrom, L. (1984) Bactericidal and Cytotoxic Effects of Hypthiocyanite-Hydrogen Peroxide Mixtures. Infection & Immunity 44: 581–6.). Elemental iodine, while also easily formed in the presence of these naturally occurring oxidants, ordinarily is not formed as an anti-infective in the body defenses against microorganisms because the concentration of iodide in tissues and body fluids, with the exception of the thyroid gland, are too low relative to chloride, the most abundant halide found in body tissues and fluids. Thus hypochlorite and chloramines are produced within the body in far greater abundance than hypoiodite and iodamines under physiological conditions.
Accordingly, it can be appreciated from the above observations that there is a need for fabricating medical devices such as cannulas, catheters and the like, and other types of implants with microbicidal, virucidal, or spermicidal activity, aimed at treating ongoing infections, preventing infections that gain access through the implanted devices, or providing contraceptive and anti-infective properties, with improved performance over current antibiotic, iodophor treatments, or contraceptive systems.